The term "impotence" has been used to signify the inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse. The term "erectile dysfunction" has been suggested as a more precise term "to signify an inability of the male to achieve an erect penis as part of the overall multifaceted process of male sexual function." Droller, M. J. et al. Impotence. Consensus Development Conference Statement, National Institutes of Health (1993).
Erectile disfunction may result from psychological causes (psychogenic erectile dysfunction) or organic causes or a combination. Organic causes include physiological, nervous, vascular and hormonal pathologies or a combination thereof.
The normal physiology of an erection involves nerve impulses which signal certain muscles to relax. These muscles, when contracted, restrict blood flow through arteries in the penis. When relaxed, the muscles permit a significant increase in blood flow. The increased blood flow engorges three groups of erectile tissue within the penis with blood and the penis becomes less flaccid. The engorged erectile tissue and the muscle structure of the penis depress adjacent veins, restricting the flow of blood out of the penis. The restriction of blood flow out of the penis increases and sustains the erection.
Deficiencies of some hormones, such as testosterone, or elevation of others, such as prolactin, can cause erectile dysfunction. Many drugs, such diuretics, antihypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs may cause erectile disfunction as a side effect. Murray, F. T. et al. Amer. J. Medical Sci. 309: 99-109 (1995).
Damage to nerves and blood vessels may also provide an organic cause for erectile dysfunction. Disease processes may involve several aspects. For example, diabetes, which causes damage to both nerves and blood vessels, can cause erectile dysfunction. A significant percent of all diabetic men will suffer from erectile dysfunction.
Methods proposed for the treatment of erectile dysfunction have included external devices, sex therapy, surgical implantation of internal prostheses, injection of drugs directly into the penis and topically applied medications. None of these approaches is entirely effective.
External devices include tourniquets (see U.S. Pat. No. 2,818,855) and externally applied vacuum erection aids. While some clinicians consider externally applied erection aids as a first option for treatment, some patients are unwilling to use such devices. O'Keefe, M., et al. Medical Clinics of North America 79: 415-434 (1995).
Symptomatic sex therapy was originally found to be effective by Masters and Johnson, but later studies have not shown as impressive results. Freudian therapy does not appear to patients to be an attractive alternative. Vickers, M. A., et al. J. Urology 149: 1258-1261 (1993).
Surgically implanted mechanical devices, such as hinged or solid rods and inflatable, spring driven or hydraulic prostheses have been used for some time.
The administration of erection effecting and enhancing drugs is taught in U.S. Pat. No. 4,127,118 to LaTorre. This patent teaches a method of treating male impotence by injecting into the penis an appropriate vasodilator, in particular, an adrenergic blocking agent or a smooth muscle relaxant to effect and enhance an erection.
More recently, U.S. Pat. No. 4,801,587 to Voss et al. teaches the application of an ointment to relieve impotence. The ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin. U.S. Pat. No. 5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl-.beta.-cyclodextrin.
Recently the effect of apomorphine on penile tumescence in male patients afflicted with psychogenic impotence has been studied. Segraves, R,T, et. al. J. Urology 145: 1174-1175 (1991). These studies show that while apomorphine can indeed induce an erection in a psychogenic male patient; the apomorphine dose required to achieve a significant erectile response is usually accompanied by nausea or other serious undesirable side effects such as hypertension, flushing and diaphoresis.
Studies measuring the bioavailability, the bioavailable dose, the rate of absorption, elimination, and metabolism for apomorphine have been reported. Muhtadi, F. J. and M. S. Hifnawy, Analytical Profile of Apomorphine Hydrochloride, in Analytical Profiles of Drug Substances, Klaus Florely Ed., Vol 20, Academic Press, Inc. New York (1991). Traditional routes of administration, such as oral tablet and liquid preparations have been shown to be relatively ineffective in establishing a blood plasma level for this drug compared to parenteral administration. However, the sublingual route of administration has been investigated for the treatment of Parkinson's disease. In that study, sublingual apomorphine was found to be about 10% bioavailable compared to parenteral administration. Deffond, D, et al. J. Neurol. Neurosurg. and Psych. 56:101-103 (1993).
Sublingual tablets are well documented in the literature since the beginning of this century. The main reason for sublingual route of drug administration is to provide a rapid onset of action of potent drugs. Another reason is to avoid the first pass metabolism by the liver. The term "controlled release" when applied to sublingual tablets is limited to a maximum of about 60 minutes. Traditional sublingual tablets are usually designed as water soluble tablets made of water soluble sugars such as sorbitol, lactose, mannitol, etc. In the literature, controlled release sublingual tablets are very scarce.
Time release sublingual medications are disclosed in U.S. Pat. No. 3,428,728 issued to Lowey. (1969), perhaps due to the limited residence time in the sublingual cavity, or poor patient compliance, or acceptance of having a foreign body under the tongue for extended periods of time.
Lowey described a controlled release sublingual tablet made by cooking gum acacia and sorbitol (by heating) till partial dryness followed by addition of citric acid, color and flavor followed by cooling. Active ingredients such as nitroglycerin, caffeine, guaiocolate, amylase or isoproterenol were then added to the pourable paste that was cast into tablets. However, Lowey's discovery cannot be applied to make tablets by compression.
The time of release for a pharmaceutical preparation is critical to the effectiveness of the drug. An immediate release of the drug such as a solution of apomorphine placed under the tongue results in an overwhelming percentage of undesirable side effects. Heaton, J. P. W. et al. Recovery of erectile function by the oral administration of apomorphine Urology 45: 200-206 (1995). The sublingual tablet of the present invention provides a relatively slow controlled drug release as compared with a conventional soluble tablet, and thus dramatically reduces the undesirable side effects of drugs such as apomorphine.
What is needed is an effective treatment of psychogenic erectile dysfunction that involves minimal mechanical distractions and unwanted side effects.